Pharmacodynamics
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Principles of Pharmacology: Pharmacodynamics Dennis Paul, Ph.D. [email protected]
Learning Objectives:
Understand the theoretical basis of drug-receptor interactions. Understand the determinants and types of responses to drug-receptor interactions. Know the four major families of receptors. Define potency and efficacy. Understand how to compare drug potency and efficacy. Understand measures of drug safety. Understand the consequences of
TEXT:
CHAPTER 2 – “PHARMACODYNAMICS: Mechanisms of Drug Action and the Relationship between Drug Concentration and Effect” – GOODMAN AND GILMAN’S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS – 10th edition
Biochemistry: L+S
LS
Biochemistry: L+S
LS
Pharmacology: L+R
LR
Biochemistry: L+S
LS
Pharmacology: L+R
LR
Response
Pharmacodynamics
Drugs:
Chemical agents that interact with components of a biological system to alter the organism’s function. Examples of such components, sites of drug action, are enzymes, ion channels, neurotransmitter transport systems, nucleic acids and receptors. Many drugs act by mimicking or inhibiting the interactions of endogenous mediators with their receptors
Receptors:
Regulatory proteins that interact with drugs or hormones and initiate a cellular response – Ion channels – G-protein coupled receptors – Receptor-enzymes – Cytosolic-nuclear receptors Act as transducer proteins – Receptor-effector signal transduction – Post-receptor signal transduction provides for amplification of the signal
Ligand-gated Ion Channels
G-protein coupled receptors
α β γ
G-protein coupled receptors Membran e
α β γ
G-protein coupled receptors
α
β γ
Receptor-enzyme Binding site
Catalytic site
Cytosolic-Nuclear receptors
Classical Receptor Occupancy Theory KA L+R
LR
Response
Stimulus
Kd L: Ligand (Drug) R: Receptor LR: Ligand-Receptor Complex KA: Affinity constant Stimulus: initial effect of drug on
Properties of drugs
Affinity: The chemical forces that cause the drug to associate with the receptor. Efficacy: The extent of functional change imparted to a receptor upon binding of a drug.
Properties of a biological system
Potency: Dose of drug necessary to produce a specified effect. – Dependent upon receptor density, efficiency of the stimulus-response mechanism, affinity and efficacy.
Magnitude of effect: Assymtotic maximal response – Solely dependent upon intrinsic efficacy. – Also called efficacy.
Determinants of Response
Intrinsic Efficacy (ε): Power of a drug to induce a response. Number of receptors in the target tissue.
Spare receptors
Some tissues have more receptors than are necessary to produce a maximal response. – Dependent on tissue, measure of response and intrinsic efficacy of the drug.
Active vs Inactive states
Active states initiate cell signaling. For any cell, there is an equilibrium between active an inactive states. The inactive state usually predominates. Each state has its own affinity.
Classification of a drug based on drug-receptor interactions:
Agonist: Drug that binds to receptors and initiates a cellular response; has affinity and efficacy. Agonists promote the active state.
Antagonist: drug that binds to receptors but cannot initiate a cellular response, but prevent agonists from producing a response; affinity, but no efficacy. Antagonists maintain the
cont.
Partial agonists: Drug that, no matter how high the dose, cannot produce a full response.
Inverse agonist: Drug that binds to a receptor to produce an effect opposite that of an agonist. Stabilizes receptors in the inactive state.
Graded dose-response curves
Individual responses to varying doses Concepts to remember: – Threshold: Dose that produces a just-noticeable effect. – ED50: Dose that produces a 50% of maximum response. – Ceiling: Lowest dose that
Dose-response curve 100
Respons e
80 60 40 20 0 0
200
400
Dose
600
800
1000
Dose-response curve 100
Respons e
80 60 40 20 0 0.1
1
10
Dose
100
1000
10000
100 80 60 40 20 0 0.1
= Agonist
1
10
100
1000
10000
100 80 60 40 20 0 0.1
= Agonist
1
10
100
1000
10000
100 80 60 40 20 0 0.1
= Agonist
1
10
100
1000
10000
100 80 60 40 20 0 0.1
= Agonist
1
10
100
1000
10000
100 80 60 40 20 0 0.1
= Agonist
1
10
100
1000
10000
100 80 60 40 20 0 0.1
= Agonist
1
10
100
1000
10000
100 80 60 40 20 0 0.1
= Agonist
1
10
100
1000
10000
Dose-response curve Ceiling
100
Respons e
80 60
ED50
40
Threshold
20 0 0.1
1
10
Dose
100
1000
10000
Full vs Partial agonists % Effect
100
Full Agonist
80 60 40 20
Partial Agonist 0 0.1
1
10
D
100
1000
10000
Full vs Partial agonists
These terms are tissue dependent – – – –
Receptor density Cell signaling apparatus Other receptors that are present Drug history
Partial agonists have both agonist and antagonist properties.
Inverse Agonist % Effect
100
Full agonist
80 60 40
Partial agonist
20 0 -20
1
1
0
1
0
0
Inverse agonist
-40
D
1
0
0
0
1
0
0
0
0
Relative Potency 100
B
A
Effec t
80 60 40 20 0 0.1
1
10
D
100
1000
10000
Relative Potency 100
A
B
Effec t
80 60 40 20 0 0.1
1
10
D
100
1000
10000
Relative Potency =ED50B/ED50A 320/3.2=100
Relative Efficacy 100
Relative Efficacy
80 60 40 20 0 0.1
1
10
100
1000
10000
Antagonists
Competitive: Antagonist binds to same site as agonist in a reversible manner. Noncompetitive: Antagonist binds to the same site as agonist irreversibly. Allosteric: Antagonist and agonist bind to different site on same receptor Physiologic: Two drugs have opposite effects through differing mechanisms
120 100 80 60 40 20 0 -10.5
= Agonist
=
-10
-9.5
-9
-8.5
-8
-7.5
-7
-6.5
-6
120 100 80 60 40 20 0 -11
= Agonist
=
-10
-9
-8
-7
-6
120 100 80 60 40 20 0 -11
= Agonist
=
-10
-9
-8
-7
-6
120 100 80 60 40 20 0 -11
= Agonist
=
-10
-9
-8
-7
-6
120 100 80 60 40 20 0 -11
= Agonist
=
-10
-9
-8
-7
-6
120 100 80 60 40 20 0 -11
= Agonist
=
-10
-9
-8
-7
-6
120 100 80 60 40 20 0 -11
= Agonist
=
-10
-9
-8
-7
-6
Competition 1200
Effect
1000 800 600
IC50
400 200 0 -11
-10
-9
-8
log [antagonist]
-7
-6
Competition 120
Effect
100
80 -11
-10
-9
-8
log [antagonist]
-7
-6
= Agonist
=
= Agonist
=
= Agonist
=
= Agonist
=
= Agonist
=
= Agonist
=
= Agonist
=
Competitive antagonists Response
100
A
B
C
10
100
1000
80 60 40 20 0 0.1
1
D
10000
Noncompetitive antagonists Response
100
A
80 60
B
40
C
20 0 0.1
1
10
D
100
1000
10000
Allosteric and Physiologic antagonists
Response can be irregular
Allosteric Antagonism
Allosteric Antagonism
Allosteric Antagonism
Allosteric Antagonism
Allosteric antagonists 1 Response
100
A
80 60 40 20 0 0.1
1
10
D
100
1000
10000
Allosteric antagonists 2 Response
100
A
80 60
B
40
C
20 0 0.1
1
10
D
100
1000
10000
Desired vs undesired effects: Indices of drug safety. Safety Index Therapeutic Index
Safety index: LD1/ED99 ED99 100 80
Sleep
Death
60 40
LD1
20
10 0K
10 K
1K
10 0
10
1
-20
0. 1
0. 00 01 0. 00 1 0. 01
0
Therapeutic index: LD50/ED50 100 80
Sleep
Death
60 40 20
10 0K
10 K
1K
10 0
10
1
-20
0. 1
0. 00 01 0. 00 1 0. 01
0
Receptor regulation
Reduced responsivity: Chronic use of an agonist can result in the receptor-effector system becoming less responsive –
eg. alpha-adrenoceptor agents used as nasal decongestants
Myasthenia gravis: decrease in number of functional acetylcholine nicotinic receptors at the neuromuscular junction.
Receptor regulation Increased responsivity: Chronic disuse of a receptor-effector system can result in an increased responsiveness upon re-exposure to an agonist.
–
– –
Denervation supersensitivity at skeletal muscle acetylcholine nicotinic receptors Thyroid induced upregulation of cardiac beta-adrenoceptors Prolonged use of many antagonists (pharmacological as well as functional)
Receptor Upregulation
Most receptors are internalized and degraded or recycled with age and use. Antagonists slow use-dependent internalization Inverse agonists stabilize the receptor in the inactive state to prevent internalization. The cell continues to produce receptors.
Learning Objectives:
Understand the theoretical basis of drug-receptor interactions. Understand the determinants and types of responses to drug-receptor interactions. Know the four major families of receptors. Define potency and efficacy. Understand how to compare drug potency and efficacy. Understand measures of drug safety. Understand the consequences of
TEXT:
CHAPTER 2 – “PHARMACODYNAMICS: Mechanisms of Drug Action and the Relationship between Drug Concentration and Effect” – GOODMAN AND GILMAN’S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS – 10th edition
Biochemistry: L+S
LS
Biochemistry: L+S
LS
Pharmacology: L+R
LR
Biochemistry: L+S
LS
Pharmacology: L+R
LR
Response
Pharmacodynamics
Drugs:
Chemical agents that interact with components of a biological system to alter the organism’s function. Examples of such components, sites of drug action, are enzymes, ion channels, neurotransmitter transport systems, nucleic acids and receptors. Many drugs act by mimicking or inhibiting the interactions of endogenous mediators with their receptors
Receptors:
Regulatory proteins that interact with drugs or hormones and initiate a cellular response – Ion channels – G-protein coupled receptors – Receptor-enzymes – Cytosolic-nuclear receptors Act as transducer proteins – Receptor-effector signal transduction – Post-receptor signal transduction provides for amplification of the signal
Ligand-gated Ion Channels
G-protein coupled receptors
α β γ
G-protein coupled receptors Membran e
α β γ
G-protein coupled receptors
α
β γ
Receptor-enzyme Binding site
Catalytic site
Cytosolic-Nuclear receptors
Classical Receptor Occupancy Theory KA L+R
LR
Response
Stimulus
Kd L: Ligand (Drug) R: Receptor LR: Ligand-Receptor Complex KA: Affinity constant Stimulus: initial effect of drug on
Properties of drugs
Affinity: The chemical forces that cause the drug to associate with the receptor. Efficacy: The extent of functional change imparted to a receptor upon binding of a drug.
Properties of a biological system
Potency: Dose of drug necessary to produce a specified effect. – Dependent upon receptor density, efficiency of the stimulus-response mechanism, affinity and efficacy.
Magnitude of effect: Assymtotic maximal response – Solely dependent upon intrinsic efficacy. – Also called efficacy.
Determinants of Response
Intrinsic Efficacy (ε): Power of a drug to induce a response. Number of receptors in the target tissue.
Spare receptors
Some tissues have more receptors than are necessary to produce a maximal response. – Dependent on tissue, measure of response and intrinsic efficacy of the drug.
Active vs Inactive states
Active states initiate cell signaling. For any cell, there is an equilibrium between active an inactive states. The inactive state usually predominates. Each state has its own affinity.
Classification of a drug based on drug-receptor interactions:
Agonist: Drug that binds to receptors and initiates a cellular response; has affinity and efficacy. Agonists promote the active state.
Antagonist: drug that binds to receptors but cannot initiate a cellular response, but prevent agonists from producing a response; affinity, but no efficacy. Antagonists maintain the
cont.
Partial agonists: Drug that, no matter how high the dose, cannot produce a full response.
Inverse agonist: Drug that binds to a receptor to produce an effect opposite that of an agonist. Stabilizes receptors in the inactive state.
Graded dose-response curves
Individual responses to varying doses Concepts to remember: – Threshold: Dose that produces a just-noticeable effect. – ED50: Dose that produces a 50% of maximum response. – Ceiling: Lowest dose that
Dose-response curve 100
Respons e
80 60 40 20 0 0
200
400
Dose
600
800
1000
Dose-response curve 100
Respons e
80 60 40 20 0 0.1
1
10
Dose
100
1000
10000
100 80 60 40 20 0 0.1
= Agonist
1
10
100
1000
10000
100 80 60 40 20 0 0.1
= Agonist
1
10
100
1000
10000
100 80 60 40 20 0 0.1
= Agonist
1
10
100
1000
10000
100 80 60 40 20 0 0.1
= Agonist
1
10
100
1000
10000
100 80 60 40 20 0 0.1
= Agonist
1
10
100
1000
10000
100 80 60 40 20 0 0.1
= Agonist
1
10
100
1000
10000
100 80 60 40 20 0 0.1
= Agonist
1
10
100
1000
10000
Dose-response curve Ceiling
100
Respons e
80 60
ED50
40
Threshold
20 0 0.1
1
10
Dose
100
1000
10000
Full vs Partial agonists % Effect
100
Full Agonist
80 60 40 20
Partial Agonist 0 0.1
1
10
D
100
1000
10000
Full vs Partial agonists
These terms are tissue dependent – – – –
Receptor density Cell signaling apparatus Other receptors that are present Drug history
Partial agonists have both agonist and antagonist properties.
Inverse Agonist % Effect
100
Full agonist
80 60 40
Partial agonist
20 0 -20
1
1
0
1
0
0
Inverse agonist
-40
D
1
0
0
0
1
0
0
0
0
Relative Potency 100
B
A
Effec t
80 60 40 20 0 0.1
1
10
D
100
1000
10000
Relative Potency 100
A
B
Effec t
80 60 40 20 0 0.1
1
10
D
100
1000
10000
Relative Potency =ED50B/ED50A 320/3.2=100
Relative Efficacy 100
Relative Efficacy
80 60 40 20 0 0.1
1
10
100
1000
10000
Antagonists
Competitive: Antagonist binds to same site as agonist in a reversible manner. Noncompetitive: Antagonist binds to the same site as agonist irreversibly. Allosteric: Antagonist and agonist bind to different site on same receptor Physiologic: Two drugs have opposite effects through differing mechanisms
120 100 80 60 40 20 0 -10.5
= Agonist
=
-10
-9.5
-9
-8.5
-8
-7.5
-7
-6.5
-6
120 100 80 60 40 20 0 -11
= Agonist
=
-10
-9
-8
-7
-6
120 100 80 60 40 20 0 -11
= Agonist
=
-10
-9
-8
-7
-6
120 100 80 60 40 20 0 -11
= Agonist
=
-10
-9
-8
-7
-6
120 100 80 60 40 20 0 -11
= Agonist
=
-10
-9
-8
-7
-6
120 100 80 60 40 20 0 -11
= Agonist
=
-10
-9
-8
-7
-6
120 100 80 60 40 20 0 -11
= Agonist
=
-10
-9
-8
-7
-6
Competition 1200
Effect
1000 800 600
IC50
400 200 0 -11
-10
-9
-8
log [antagonist]
-7
-6
Competition 120
Effect
100
80 -11
-10
-9
-8
log [antagonist]
-7
-6
= Agonist
=
= Agonist
=
= Agonist
=
= Agonist
=
= Agonist
=
= Agonist
=
= Agonist
=
Competitive antagonists Response
100
A
B
C
10
100
1000
80 60 40 20 0 0.1
1
D
10000
Noncompetitive antagonists Response
100
A
80 60
B
40
C
20 0 0.1
1
10
D
100
1000
10000
Allosteric and Physiologic antagonists
Response can be irregular
Allosteric Antagonism
Allosteric Antagonism
Allosteric Antagonism
Allosteric Antagonism
Allosteric antagonists 1 Response
100
A
80 60 40 20 0 0.1
1
10
D
100
1000
10000
Allosteric antagonists 2 Response
100
A
80 60
B
40
C
20 0 0.1
1
10
D
100
1000
10000
Desired vs undesired effects: Indices of drug safety. Safety Index Therapeutic Index
Safety index: LD1/ED99 ED99 100 80
Sleep
Death
60 40
LD1
20
10 0K
10 K
1K
10 0
10
1
-20
0. 1
0. 00 01 0. 00 1 0. 01
0
Therapeutic index: LD50/ED50 100 80
Sleep
Death
60 40 20
10 0K
10 K
1K
10 0
10
1
-20
0. 1
0. 00 01 0. 00 1 0. 01
0
Receptor regulation
Reduced responsivity: Chronic use of an agonist can result in the receptor-effector system becoming less responsive –
eg. alpha-adrenoceptor agents used as nasal decongestants
Myasthenia gravis: decrease in number of functional acetylcholine nicotinic receptors at the neuromuscular junction.
Receptor regulation Increased responsivity: Chronic disuse of a receptor-effector system can result in an increased responsiveness upon re-exposure to an agonist.
–
– –
Denervation supersensitivity at skeletal muscle acetylcholine nicotinic receptors Thyroid induced upregulation of cardiac beta-adrenoceptors Prolonged use of many antagonists (pharmacological as well as functional)
Receptor Upregulation
Most receptors are internalized and degraded or recycled with age and use. Antagonists slow use-dependent internalization Inverse agonists stabilize the receptor in the inactive state to prevent internalization. The cell continues to produce receptors.
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